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·         Drugs typically exert their effects by interacting with a macromolecule (receptor)
·         Drug-receptor interactions have been important in:
o    new drug development
o    therapeutic decisions
o    Determines quantitative relationships between drug dose and pharmacological effect.
o    Determines drug action selectivity
o    Mediates antagonist (blocking) as well as agonist (activating) effects
o    Usually proteins, specifically regulatory proteins -- mediating effects of:
§  neurotransmitters
§  autacoids (histamine, serotonin, endogenous peptides, prostaglandins, leukotrienes)
§  hormones
o    Some receptors are enzymes --may be inhibited or occasionally activated by drugs
§  e.g. dihydrofolate reductase (receptor) -- methotrexate(drug inhibitor)
o    Other receptors are transport proteins:
§  e.g. Na/K ATPase (receptor for digitalis glycosides {digoxin (Lanoxin, Lanoxicaps), digitoxin(Crystodigin)}
o    Still other receptors are structural proteins:
§  tubulin-- receptor for certain anticancer drugs and anti-inflammatory drugs


Signal Transduction
·         Signal transduction is the process by which extracellular inputs (drug-receptor interactions) leads to intracellular messages that modulate cellular physiology.
·         Molecular mechanisms of signal transduction:
1.     Drug crosses the cellular membrane: activates an intracellular receptor
2.     Transmembrane receptor protein: intracellular enzyme activity affected by drug binding to a site on the enzyme that can alter its activity.
3.     Drug- transmembrane receptor protein complex binds and stimulates a second protein, such as a protein tyrosine kinase.
§  A tyrosine kinase enzyme promotes phosphorylation of proteins (at the aminoacid tyrosine site)
4.     Drug binding to a transmembrane ion channel changes the ion channel conductance property--affecting membrane potential
5.     Agonist drug binding to a transmembrane receptor causes stimulation of a GTP-binding signal transducer protein (G protein) -- leading to an increase in intracellular second messenger that results in many secondary intracellular responses.
o    lipid-soluble drugs, after crossing the cell membrane barrier, interact with intracellular receptors. Example:nitric oxide (NO)-- stimulates guanylyl cyclase, increasing cGMP levels
o    The agents below bind to DNA response elements that control transcription:
§  thyroid hormone
§  corticosteroids
§  mineralocorticoids
§  sex steroids
§  vitamin D
·         Drug (ligand)-regulated transmembrane enzymes (may involve receptor tyrosine kinases)
o    mediate signaling first step by:
§  insulin
§  epidermal growth factor (EGF)
§  platelet-derived growth factor (PDGF)
§  atrial natriuretc factor (ANF)
o    activated by many diverse peptide ligands:
§  growth hormone
§  erythropoietin
§  some interferons
§  other growth and differentiation regulators
·         Ligand-gated Channels
o    Introduction: Many drugs mimic or block the action of normally occurring (endogenous) agents that effect ion conductance of membrane integrated ion channels.
o    Introduction: Many drugs mimic or block the action of normally occurring (endogenous) agents that effect ion conductance of membrane integrated ion channels.
o    Endogenous ligand include:
§  acetylcholine
§  gamma amino butyric acid (gaba, inhibitory action)
§  excitatory amino acids:
§  glycine
§  aspartate
§  glutamate
o    Receptor example: nicotinic acetylcholine receptor:
§  Activation:
§  acetylcholine binds
§  receptor channel opens
§  Na+ enters (down its concentration and electrical gradient)
§  depolarization occurs (EPSP)
§  Other multisubunit ligand-gated examples:
§  glutamate receptor
§  GABAA receptor
§  benzodiazepines (diazepam {Valium} enhance chloride conductance by allosteric modification of the GABAA receptor
§  glycine receptor
§  5-HT3 receptor


G proteins and Second Messengers
·         Second messenger effects:
o     increases in cAMP
o     Ca2+ concentration changes
o     phosphoinositides effects
·         Four steps:
1.                  drug binding
2.                  G protein activation (cytoplasmic side)
3.                  activity of effector (ion channel or enzyme) changed
4.                  intracellular second messenger concentration changes
§  cAMP: effector enzyme -- adenylyl cyclase, converting ATP to cAMP
§  Adenylyl cyclase activated by a G protein
§  G proteins may be activated by many neurotransmitters and hormones
o     The magnitude of receptors-mediated responses decrease with repeated drug administration.
o     Desensitization is often reversible.
  • Concentration-Response Relationship
    • Drug effect (assuming the drug acts reversibly with the receptor) is thought proportional to the number of occupied receptors.
    • Drug (D) + Receptor (R) « DR leads to  Effect (equation 1)
    • Observed Drug Effect = (maximal drug effect · [D]) / Kd + [D] (equation 2)
      • where [D] is the free drug concentration;
      • Kd is the dissociation constant for the drug-receptor (DR) complex
      • Equation 2 describes drug potency -- the dependency of drug effect on drug concentration
    • Drug antagonists bind either to the receptor itself or to some component of the effector mechanism to prevent the agonist action.
      • Antagonists themselves have no effect.
      • If the antagonist-mediated inhibition can be overcome by increasing agonist concentration ultimately reaching the same maximal effect, the antagonist is termed competitive.
        • Competitive inhibition is based on reversible binding at receptor sites.
        • With competitive inhibition, the dose-effect curve will be shifted to the right.
        • With competitive inhibition, the maximal drug effect will not be affected.
      • By contrast, a non-competitive antagonist will prevent the agonist from producing a maximal effect (and any agonist concentration)
        • If the antagonist binds at the active site and is a reversible antagonist, the inhibition will be competitive.
        • If the antagonist binds that the active site and is an irreversible antagonist, the inhibition will be noncompetitive.


Concepts for signaling mechanisms and drug action
·         Intracellular receptors:
o    lipid-soluble drugs, after crossing the cell membrane barrier, interact with intracellular receptors. Example: nitric oxide (NO)-- stimulates guanylyl cyclase, increasing cGMP levels
o    Numerous agents can bind to DNA response elements, thus controlling transcription.
·         Hormones that act through gene transcription may take thirty minutes to several hours lag time before effect begins and may take a long time to dissipate.


 Transmembrane Sites of Action
  • intracellular signaling may be mediated initially by binding substances such as those noted below.
    •  Insulin
    •  Epidermal growth factor (EGF)
    •  Platelet-derived growth factor (PDGF)
    •  Atrial natriuretc factor (ANF)


Ligand-gated Channels
·         Introduction:Many drugs mimic or block the action of normally occurring (endogenous) agents that effect ion conductance of membrane integrated ion channels.
  • Endogenous ligand include:
    • acetylcholine
    • gamma amino butyric acid (gaba, inhibitory action)
    • excitatory amino acids:
      •  glycine
      •  aspartate
      •  glutamate
  • Receptor example: nicotinic acetylcholine receptor:
    • Activation:
      • acetylcholine binds
      • receptor channel opens
      • Na+ enters (down its concentration and electrical gradient)
      • depolarization occurs (EPSP)


G Protein Coupling
·           G-protein coupled receptors are involved in signal transduction for:
o    biogenic amines
o    eicosanoids
o    peptide hormones
·         G-Protein systems influence other important regulatory molecules, such as:
o    adenylyl cyclase (cAMP)
o    phospholipases A2, C and D.
o    Ca 2+, K+, Na+ channels
o    transport proteins

·         cAMP: intracellular second messenger
o    Hormone response mediator:
§  carbohydrate breakdown (liver)
§  triglyceride breakdown (fat cells)
§  conservation of water (renal -- vasopressin)
§  calcium homeostasis
§  cardiac chronotropic (rate) and inotropic (contractility) state
§  adrenal and sex steroids regulation (responding to corticotropin and follicle stimulating hormone)
§  smooth muscle relaxation
§  other endocrine/neural effects
o    Specificity:
§  due to the presence of different protein substrates, associated with different cell types:
·         Liver:
·         Fat cells
·         Smooth muscle
o    Termination of effect:
§  Proteins which were phosphorylated by cAMP dependent processes are dephosphorylated by the action of specific and nonspecific enzymes (phosphatases).
§  cAMP is degraded to 5'-AMP (inactive) by cyclic nucleotide phosphodiesterases.
·         some pharmacological effects of caffeine, theophylline, and other methylxanthines may be due to competitive inhibition of cAMP degradation
o    G protein or tyrosine kinase receptor linked
o    Central Steps:
§  stimulation of phospholipase C
§  subsequent cascade of steps results in:increased intracellular calcium enhances calcium binding to calmodulin
§  calmodulin regulates enzyme activities, including calcium-dependent protein kinases.
o    cGMP-based signal transduction may be more limited than cAMP-based systems.
o    Intestinal mucosa and vascular smooth muscle:
o    Vascular smooth muscle
o    activation of calcium-phosphoinositide and cAMP signaling systems may produce complementary or opposing results:
§  Opposition: vasopressor induced smooth muscle contraction: IP3-mediated increase in calcium; compounds that cause smooth muscle relaxation often do so by increasing cAMP concentration.
§  Complementary: cAMP and phosphoinositides second messenger systems act both to stimulate hepatic glucose release.


  • Blood vessel endothelium is required for ACh-mediated smooth muscle relaxation.
  • The endothelial cell layer modulates vessel responsiveness to autonomic and hormonal influences.
  • Endothelial cell elaborate endothelium-derived relaxing factor (EDRF,NO) and a contracting factor.
    • Pharmacological actions of:
    • serotonin
    • histamine
    • bradykinin
    • purines
    • thrombin are mediated to some degree by stimulation of NO release.
  • EDRF is nitric oxide.
  • Endothelial-released nitric oxide:
1.     diffuses into vascular smooth muscle
2.     increases cGMP
3.     facilitates vascular smooth muscle relaxation

Catecholamine Refractoriness
  • Following exposure to catecholamines, there is a progressive loss of the ability of the target site to respond to catecholamines. This phenomenon is termed tachyphylaxis, desensitization or refractoriness.
  • Regulation of catecholamine responsiveness occurs at several levels including receptors, G-proteins, adenylyl cyclase, and cyclic nucleotide phosphodiesterase.
  • Characteristics of refractoriness depends on the nature and extent of involvement of the above components.



·         Graded dose-response curves (plotted directly (no log transform) often resemble a Michaelis-Menten curves in which substrate (x-axis) is plotted against reaction velocity (y-axis)



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Pharmacology (0)

1:03 PM by . , under

Pharmacology may be defined as the study of drugs.
The word pharmacology has been derived from two Greek words
Pharmakon means drug
Logos         means study



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EARN THROUGH INTERNET (0)

12:44 PM by . , under



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